Protein misfolding and aggregation is a common thread behind many neurodegenerative diseases including Alzheimer's disease (AD), Lewy Body Dementia (LBD), and Parkinson's disease (PD) among others. While each disease has been primarily associated with aggregation of a specific protein; beta-amyloid (abeta) with AD, tau with AD and other tauopathies, alpha-synuclein (-syn) with PD and LBD, more than one protein is likely to misfold and aggregate in brain tissue complicating diagnosis and treatment strategies. Aggregation of another neuronal protein, TDP-43, has been strongly correlated with amyotrophic lateral sclerosis (ALS) and Frontal Temporal Dementia (FTD) and has also been associated with traumatic brain injury and AD among other neurodegenerative disorders. Since cellular stress induced by misfolding and aggregation of one protein such as abeta may well lead to misfolding and aggregation of other proteins such as -syn, tau and TDP-43, the presence of multiple misfolded proteins in different diseases should be expected. Therefore characterizing which aggregated protein species are correlated with different stages of each disease would greatly facilitate development of better diagnostic and treatment strategies. We have generated several well characterized reagents that specifically recognize different aggregated species of abeta and -syn, and have demonstrated that the reagents recognize aggregated species occurring in tissue from diseased brains, but not healthy brains, and that the reagents can have disease specificity as well. Here we will develop and test similar reagents for detecting specific forms of TDP-43 that are present in FTD and ALS brain tissue. PUBLIC HEALTH RELEVANCE: Protein misfolding and aggregation into toxic species are common mechanisms behind several neurodegenerative diseases including Alzheimer's, Parkinson's, Frontal Temporal Dementia and Amyotrophic lateral sclerosis. However it is not known how, when or where protein aggregation occurs during the progression of these devastating diseases. This project focuses on developing and using reagents to detect and localize different misfolded forms of the protein TDP-43 which has been implicated in several different neurodegenerative diseases. The project has direct applications to several neurodegenerative diseases as well as traumatic brain injury patients.